Expansion
Agonists downregulate receptors; antagonists upregulate them
Expansion
Downregulation follows sustained agonist exposure: receptors are internalised, so the response falls. Upregulation follows sustained antagonist exposure, so the tissue becomes supersensitive.
- Tachyphylaxis - rapid tolerance over minutes to hours, as with ephedrine and repeated GTN
- Tolerance - gradual, over days to weeks
- Rebound - exaggerated response on withdrawal, from upregulated receptors
“Agonists downregulate, antagonists upregulate.” That rule predicts most withdrawal syndromes.
Clinical consequences
- Nitrate tolerance: prevented by an 8 to 12 hour nitrate free interval, usually overnight
- Beta blocker withdrawal: abrupt cessation causes rebound tachycardia, hypertension and angina, occasionally infarction. Taper them
- Opioids: tolerance develops to analgesia, euphoria and respiratory depression but not to constipation or miosis, which is why laxatives are needed indefinitely
- Benzodiazepines: tolerance and dependence, with rebound anxiety, insomnia and seizures on abrupt withdrawal
- Corticosteroids: adrenal suppression, requiring tapering and sick day rules
Salbutamol tolerance is one reason that regular short acting beta agonist use without an inhaled corticosteroid is associated with worse asthma outcomes.